Despite the phenomenal success of antibiotics and vaccines, infectious diseases remain[unreadable] one of the leading cause of death worldwide. The emergence of multidrug-resistant[unreadable] bacteria has created a situation in which there are few or no options for treating certain[unreadable] infections. The intrinsic limitations of existing vaccines (cost, safety, shelf-life, etc.) and[unreadable] the current trend in major pharmaceutical companies to abandon antibiotic and vaccine[unreadable] development programs create an alarming situation with potentially catastrophic public[unreadable] health consequences.[unreadable] The radical solution for this global biomedical problem and the goal of the[unreadable] proposed research is the development of conceptually new approaches to prevent and[unreadable] treat infectious diseases.[unreadable] One general strategy is to create a new type of fully synthetic antimicrobials for[unreadable] which it would be intrinsically difficult for bacteria to develop resistance. At least one[unreadable] prototype, a chemical platform based on 5-aminonaphthalenesulfonamides (ANSA), has[unreadable] been designed in our laboratory as a proof-of-principle. Unlike the majority of antibiotics[unreadable] that target individual macromolecules, ANSA compounds irreversibly damage various[unreadable] proteins at once, thus rapidly killing a target cell. This process requires nitric oxide (NO).[unreadable] Endogenous NO is sufficient to render bacteria susceptible to ANSA, and exogenous NO[unreadable] (e.g. from macrophages) further stimulates the bactericidal effect. The combinatorial[unreadable] selection of the most potent ANSA and related compounds will be carried out to define[unreadable] the specificity for different pathogenic bacterial species.[unreadable] The second general approach involves creating probiotic-based vaccines.[unreadable] Probiotics are live bacteria that colonize or temporarily survive in the host, while[unreadable] conferring beneficial effect on its health. Probiotics that stably and controllably secrete or[unreadable] display antigens for various pathogens could effectively serve as self-sustaining vaccines.[unreadable] As a proof-of-principle we will engineer probiotic strains that upon oral administration to[unreadable] mice will induce a proper immune response rendering animals resistant to otherwise[unreadable] lethal infections.